ES2299074T3 - USEFUL NAFTALEN DERIVATIVES AS LEGANDS OF THE RECEIVER 3 OF HISTAMINE. - Google Patents

Abstract

Compounds of the general formula in which R1 is selected from the group consisting of hydrogen, C1-C8 alkyl, phenyl unsubstituted or substituted by one or two moieties independently selected from each other from the group consisting of C1-C8 alkyl, halogenoalkoxy C1 -C8 and C1-C8 hydroxyalkyl, phenyl-C1-C8 alkyl, wherein the phenyl ring is unsubstituted or substituted by one or two moieties independently selected from each other from the group consisting of C1-C8 alkyl, halogen, alkoxy C1-C8 and hydroxy C1-C8 alkyl, and (C1-C8 alkoxy) alkyl; R2 is selected from the group consisting of hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 cycloalkylalkyl, C1-C8 hydroxyalkyl, (C1-C8 alkoxy) alkyl, (C1-C8 alkyl) sulfanylalkyl, di (C1 alkyl -C8) aminoalkyl, unsubstituted phenyl or substituted by one or two moieties independently selected from each other from the group consisting of C1-C8 alkyl, halogen, C1-C8 alkoxy and hydroxy C1-C8 alkyl, phenyl-C1-C8 alkyl, in wherein the phenyl ring is unsubstituted or substituted by one or two moieties independently selected from each other from the group consisting of C1-C8 alkyl, halogen, C1-C8 alkoxy and C1-C8 hydroxyalkyl, unsubstituted pyrrolidinyl or substituted by a selected moiety between C1-C8 alkyl or halogen, C1-C8 heteroarylalkyl, in which the heteroaryl ring is unsubstituted or substituted by one or two C1-C8 alkyl moieties, and C1-C8 heterocyclylalkyl, in which the heterocyclic ring is unsubstituted or substituted by one or two C1-C8 alkyl moieties; or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 links, saturated or partially unsaturated, optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, said saturated heterocyclic ring is unsubstituted or substituted by one, two or three moieties independently selected from each other from the group consisting of C1-C8 alkyl, halogen, halogenoalkyl, hydroxy, hydroxy C1-C8 alkyl, C1-C8 alkoxy, oxo, phenyl, benzyl, pyridyl , dialkylamino, carbamoyl, C1-C8 alkylsulfonyl and (C1-C8 halogenoalkyl) -carbonylamino, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or substituted by one, two or three moieties independently selected from each other between C1 alkyl -C8, C1-C8 alkoxy and halogen; A is chosen from where m is 0, 1 or 2; n is 0, 1 or 2; R3 is hydrogen or lower alkyl; R9 and R10 independently of each other are chosen from hydrogen or lower alkyl; t is 1 or 2; R4 is hydrogen or C1-C8r alkyl; X is O, S or N-R8; R8 being hydrogen or C1-C8 alkyl; p is 0, 1 or 2; R5 is C1-C8 alkyl or C3-C7 cycloalkyl; q is 0, 1 or 2; R6 is C1-C8 alkyl; s is 0, 1 or 2; R7 is C1-C8 alkyl; and pharmaceutically acceptable salts thereof.

Description

Naphthalene derivatives useful as ligands of histamine receptor 3.

The present invention relates to new naphthalene derivatives, to obtain them, to compositions pharmaceuticals that contain them and their use as medicines. The active compounds of the present invention are Useful for treating obesity and other disorders.

In particular, the present invention relates to compounds of the general formula

one

in the that

R1

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, lower halogenoalkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower, and

quad

(lower alkoxy) alkyl;

R2

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

cycloalkyl,

quad

lower cycloalkylalkyl,

quad

lower hydroxyalkyl,

quad

(lower alkoxy) alkyl,

quad

(lower alkyl) sulfanylalkyl,

quad

di (alkyl lower) aminoalkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

pyrrolidinyl unsubstituted or substituted by a residue chosen from lower alkyl and halogen,

quad

lower heteroarylalkyl, in which the ring heteroaryl is unsubstituted or substituted by one or two moieties lower alkyl, and

quad

lower heterocyclyl alkyl, in which the ring heterocyclic is unsubstituted or substituted by one or two moieties lower alkyl; or

R1 and R2 together with the nitrogen atom to which they are attached form a ring heterocyclic 4, 5, 6 or 7 links, saturated or partially unsaturated optionally containing another heteroatom chosen between nitrogen, oxygen and sulfur, said heterocyclic ring saturated is unsubstituted or substituted by one, two or three remains chosen independently from each other among the group formed by lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl and (lower halogenoalkyl) carbonylamino, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or replaced by one, two or three remains chosen independently each other between lower alkyl, lower alkoxy and halogen;

TO

choose between

2

in the that

m

it is 0, 1 or 2;

n

it is 0, 1 or 2;

R 3

it is hydrogen or lower alkyl;

R 9 and R 10 with independence from each other are chosen between hydrogen and alkyl lower;

t

it is 1 or 2;

R 4

it is hydrogen or lower alkyl;

X

it is O, S or N-R 8; R8 being hydrogen or lower alkyl;

p

it is 0, 1 or 2;

R 5

it is lower alkyl or cycloalkyl;

that

it is 0, 1 or 2;

R 6

it is lower alkyl;

s

it is 0, 1 or 2;

R 7

it is lower alkyl;

and pharmaceutically salts acceptable of same.

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The compounds of formula I are antagonists and / or inverse agonists of histamine receptor 3 (receptor H3).

Histamine (2- (4-imidazolyl) ethylamine) is one of the aminergic neurotransmitters that is widely distributed e.g. through the gastrointestinal tract (Burks, in Johnson LR (coord.), Physiology of the Gastrointestinal Tract, Raven Press , NY, 1994, pp. 211-242) and regulates a wide variety of digestive pathophysiological events, for example gastric acid secretion, intestinal motility (Leurs et al., Br. J. Pharmacol. 1991, 102 , pp. 179-185), vasomotor responses, inflammatory bowel responses and allergic reactions (Raithel et al., Int. Arch. Allergy Immunol. 1995, 108 , 127-133). In the brain of mammals histamine is synthesized in histamine cell bodies that are centralized in the tuberomamillary nucleus of the posterior basal hypothalamus. From there they project to several brain regions (Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81 , 2572-2576; Inagaki et al., J. Comp. Neurol. 1988, 273 , 283-300) .

According to current knowledge, histamine intervenes in all the mentioned actions, both in the SNC and on the periphery through four different receivers of the histamine, the H1, H2, H3 and H4 receptors of histamine.

H3 receptors are predominantly located in the central nervous system. As self-receptors, H3 receptors constitutively inhibit the synthesis and secretion of histamine in histaminergic neurons (Arrang et al., Nature 1983, 302 , 832-837; Arrang et al., Neuroscience 1987, 23 , 149-157 ). As heteroreceptors, they also modulate the release of other neurotransmitters, such as acetylcholine, dopamine, serotonin and norepinephrine, among others, both in the central nervous system and in the peripheral organs, such as the lungs, the cardiovascular system and the gastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982, 107 , 919-923; Blandina et al., in The Histamine H3 Receptor (Leurs, RL and Timmermann, H., coord., 1998, pp. 27-40, Elsevier, Amsterdam, Netherlands.) H3 receptors are constitutively active, this means that even without exogenous histamine, the receptor is activated tonic.In the case of an inhibitor receptor, for example the H3 receptor, this inherent activity causes tonic inhibition of neurotransmitter release, so it may be important that the H3R receptor antagonist has inverse agonist activity both to block the effects of exogenous histamine and to Move the recipient from its constitutively active (inhibitory) form to a neutral state.

The wide distribution of H3 receptors in the mammalian CNS indicates the physiological role of this receiver. Therefore the therapeutic potential has been proposed as a goal of developing new drugs for several indications.

H3 receptor ligands are described, by example, in WO 2004/043458.

The administration of H3R ligands - whether as antagonists, inverse agonists, agonists or partial agonists - can influence histamine levels or secretion of neurotransmitters in the brain and periphery and thus may be useful for the treatment of various disorders Such disorders include obesity, (Masaki et al., Endocrinol. 2003, 144 , 2741-2748; Hancock et al., European J. of Pharmacol. 2004, 487 , 183-197), cardiovascular disorders, for example infarction Acute myocardium, dementia and cognitive disorders, such as attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease, neurological disorders such as schizophrenia, depression, epilepsy, Parkinson's disease and seizures or convulsions, sleep disorders, narcolepsy, pain, gastrointestinal disorders, vestibular dysfunction, for example Meniere's disease, drug abuse and nausea (Timmermann, J. Med. Chem. 1990, 33 , 4-11) .

It is therefore an object of the present invention develop antagonists or inverse agonists of H3 receptors selective and direct action. Such antagonists / agonists inverses are useful as therapeutically active substances, in special for the treatment and / or prevention of diseases associated with modulation of H3 receptors.

In the present description, the term "alkyl", alone or in combination with other groups, means a monovalent saturated, straight chain aliphatic hydrocarbon moiety or branched, which has one to twenty carbon atoms, with preference of one to sixteen carbon atoms, with greater preference of one to ten carbon atoms.

The term "lower alkyl" or "alkyl C_ {1} -C_ {8} ", alone or in combination, means a straight or branched chain alkyl moiety that has from 1 to 8 carbon atoms, preferably an alkyl moiety of linear or branched chain having 1 to 6 carbon atoms and with special preference a straight chain alkyl moiety or branched that has 1 to 4 carbon atoms. Are examples of C 1 -C 8 straight chain alkyl moieties or branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl isomers, isomers of hexyl, isomers of heptyl and isomers of octyl, with preferably methyl and ethyl and with special preference the methyl.

The term "cycloalkyl" or "cycloalkyl C_ {3-7} "means a carbocyclic challenge saturated having 3 to 7 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.  Especially preferred are cyclopropyl, cyclopentyl and cyclohexyl

The term "lower cycloalkylalkyl" or "(C 3-7 cycloalkyl) -alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen of the lower alkyl moiety is substituted by cycloalkyl A preferred example is cyclopropylmethyl.

The term "alkoxy" means the this R'-O-, in which R 'is alkyl. The term "alkoxy lower "means the remainder R'-O-, in which R ' it is lower alkyl and the term "lower alkyl" has the meaning defined above. Examples of alkoxy moieties are lower eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, with Methoxy and ethoxy preference and especially methoxy.

The term "(alkoxy lower) -alkyl "o" (alkoxy C 1-8) - alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen from the lower alkyl moieties has been replaced by a alkoxy moiety, preferably methoxy or ethoxy. Among the remains (lower alkoxy) preferred alkyl are the 2-methoxyethyl and the 3-methoxypropyl.

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The term "alkylsulfanyl" or "C 1-8 alkylsulfanyl" means the rest R'-S-, in which R 'is lower alkyl and the term "lower alkyl" has the meaning defined previously. Examples of alkylsulfanyl moieties are among others. methylsulfanyl and ethylsulfanyl.

The term "(alkyl lower) -sulfanylalkyl "o" (alkyl C 1-8) - sulfanylalkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen from the lower alkyl moieties has been replaced by a alkylsulfanyl moiety, preferably methylsulfanyl. An example of preferred (lower alkyl) sulfanylalkyl alkyl is the 2-methylsulfanylethyl.

The term "halogen" means fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

The term "lower halogenoalkyl" or "C 1-8 halogenoalkyl" means moieties lower alkyl already defined above in which at least one of the hydrogen atoms of the lower alkyl moiety is substituted by a halogen atom, preferably fluorine or chlorine, with special preference for fluorine. Between the alkyl groups Preferred halogenated lower are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, being preferred in Special trifluoromethyl.

The term "lower halogenoalkoxy" or "C 1-8 halogenoalkoxy" means moieties lower alkoxy already defined above in which at least one of the hydrogen atoms of the lower alkoxy moiety has replaced by a halogen atom, preferably fluorine or chlorine, with special preference fluorine. Among the remains alkyl Lower halogenated are trifluoromethoxy, difluoromethoxy, fluoromethoxy and chloromethoxy, with the trifluoromethoxy.

The term "lower hydroxyalkyl" or "C 1-8 hydroxyalkyl" means moieties lower alkyl already defined above in which at least one of the hydrogen atoms of the lower alkyl moiety is replaced by a hydroxy moiety. They are examples of remains lower hydroxyalkyl among others hydroxymethyl and the hydroxyethyl.

The term "dialkylamino" means the remainder -NR'R '', in which R 'and R' 'are lower alkyl and the term "lower alkyl" has the meaning defined above. A preferred dialkylamino moiety is dimethylamino.

The term "di (alkyl lower) aminoalkyl "or" di (alkyl C 1-8) - amino-alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen of the lower alkyl moiety is substituted by a moiety dialkylamino, preferably dimethylamino. A rest Preferred di (lower alkyl) aminoalkyl is the 3-dimethylaminopropyl.

The term "carbamoyl" means the rest -CO-NH2.

The term "(halogenoalkyl lower) carbonylamino "means the rest -NH-CO-halogenoalkyl lower, in the one that "lower halogenoalkyl" has the definite meaning previously.

The term "phenyl-alkyl lower "or" phenyl-alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms hydrogen of the lower alkyl moiety is substituted by a phenyl residue. The phenyl-lower alkyl moieties Preferred are benzyl and phenethyl.

The term "heteroaryl" means a 5 or 6 link aromatic ring that can contain one, two or three atoms chosen from nitrogen, oxygen and / or sulfur. They are examples of heteroaryl moieties, among others, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl and pyrrolyl. They are especially preferred are thienyl and pyridyl.

The term "heteroaryl-alkyl lower "or" heteroaryl-alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen of the lower alkyl moiety is substituted by a group heteroaryl already defined above.

The term "heterocyclyl" means a 5 or 6 link ring, saturated or partially unsaturated, which it can have one, two or three atoms chosen from nitrogen, oxygen and / or sulfur. Examples of heterocyclic rings include the piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl and thiamorpholinyl. Preferred heterocyclic moieties are the piperidinyl, morpholinyl and pyrrolidinyl.

The term "heterocyclyl-lower alkyl" or "heterocyclyl-alkyl C 1-8 "means lower alkyl moieties already defined above in which at least one of the atoms of hydrogen of the lower alkyl moiety is substituted by a moiety heterocyclic already defined above.

The expression "form a heterocyclic ring saturated 4, 5, 6 or 7 links, optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur "means a saturated N-heterocyclic ring, which optionally it can have another nitrogen, oxygen and sulfur atom, for example azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl. A "heterocyclic ring of 4, 5, 6 or 7 partially unsaturated links "means a ring heterocyclic already defined above that has a double bond, for example 2,5-dihydropyrrolyl or the 3,6-dihydro-2H-pyridinyl. The heterocyclic ring may be unsubstituted or substituted by one, two or three remains independently selected from each other lower alkyl, lower alkoxy and oxo. Heterocyclic ring it can also be condensed with a phenyl ring, said ring phenyl is unsubstituted or substituted by one, two or three residues independently chosen from each other among lower alkyl, alkoxy lower and halogen. An example of such a heterocyclic ring condensate is the 3,4-dihydro-1H-isoquinoline.

The term "pharmaceutically salts acceptable "means those that retain effectiveness Biological and properties of free bases or acids free, which are not annoying either in a biological sense or in any way other sense The salts are formed with inorganic acids, by example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably acid hydrochloric or organic acids, for example acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, acid ethanesulfonic acid, p-toluenesulfonic acid, acid salicylic, N-acetylcysteine and the like. These salts can also be obtained by adding an inorganic base or of an organic base on a free acid. The salts derived from an inorganic base include, but is not limited to: salts of sodium, potassium, lithium, ammonium, calcium and magnesium and Similar. Salts derived from organic bases include, but not are limited to: salts of primary, secondary and tertiary amines, of substituted amines, including substituted amines of origin Natural, cyclic amines and ion exchange resins basic, for example isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and Similar. The compound of the formula I may also be present in the form of zwitterion. The salts pharmaceutically Acceptable compounds of the formula I are preferably Special hydrochloride salts.

The compounds of the formula I also be solvated, eg hydrated. Solvation can be done in the course of the manufacturing process or it can take place e.g. consequence of the hygroscopic properties of a compound of the Formula I initially anhydrous (hydration). The term sales Pharmaceutically acceptable also includes solvates Physiologically acceptable.

"Isomers" are compounds that have identical molecular formulas, but which differ in nature and  the order of their atoms or in the arrangement of said atoms in the space. Isomers that differ in the arrangement of their atoms in space they are called "stereoisomers". The stereoisomers that are not mirror images of each other are they call "diastereoisomers" and the stereoisomers that are mirror images that match exactly when you put one on on another they are called "enantiomers" or, sometimes, optical isomers A carbon atom attached to four substituents Non-identical is called "chiral center."

The present invention relates in detail to compounds of the general formula

3

in the that

R1

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, lower halogenoalkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower, and

quad

(lower alkoxy) alkyl;

R2

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

cycloalkyl,

quad

lower cycloalkylalkyl,

quad

lower hydroxyalkyl,

quad

(lower alkoxy) alkyl,

quad

(lower alkyl) sulfanylalkyl,

quad

di (alkyl lower) aminoalkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

pyrrolidinyl unsubstituted or substituted by a residue chosen from lower alkyl or halogen,

quad

lower heteroarylalkyl, in which the ring heteroaryl is unsubstituted or substituted by one or two moieties lower alkyl, and

quad

lower heterocyclyl alkyl, in which the ring heterocyclic is unsubstituted or substituted by one or two moieties lower alkyl; or

R1 and R2 together with the nitrogen atom to which they are attached form a ring heterocyclic 4, 5, 6 or 7 links, saturated or partially unsaturated optionally containing another heteroatom chosen between nitrogen, oxygen and sulfur, said heterocyclic ring saturated is unsubstituted or substituted by one, two or three remains chosen independently from each other among the group formed by lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl and (lower halogenoalkyl) carbonylamino, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or replaced by one, two or three remains chosen independently each other between lower alkyl, lower alkoxy and halogen;

TO

choose between

4

in the that

m

it is 0, 1 or 2;

n

it is 0, 1 or 2;

R 3

it is hydrogen or lower alkyl;

R 9 and R 10 with independence from each other are chosen from hydrogen or alkyl lower;

t

it is 1 or 2;

R 4

it is hydrogen or lower alkyl;

X

it is O, S or N-R 8; R8 being hydrogen or lower alkyl;

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p

it is 0, 1 or 2;

R 5

it is lower alkyl or cycloalkyl;

that

it is 0, 1 or 2;

R 6

it is lower alkyl;

s

it is 0, 1 or 2;

R 7

it is lower alkyl;

and pharmaceutically salts acceptable of same.

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In one embodiment, the present invention refers to compounds of the formula I of the invention, in the that

R1

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently of each other from lower alkyl, lower halogenoalkoxy or lower hydroxyalkyl, and

quad

phenyl-lower alkyl in which the phenyl ring may be unsubstituted or substituted by one or two remains chosen independently of each other from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl;

R2

you choose between the group formed by hydrogen,

quad

lower alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently of each other from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl, and

quad

phenyl-lower alkyl in which the phenyl ring may be unsubstituted or substituted by one or two remains chosen independently of each other from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl; or

R1 and R2 together with the nitrogen atom to which they are attached form a ring 5 or 6-link saturated heterocyclic containing optionally another heteroatom chosen from nitrogen, oxygen and sulfur, said saturated heterocyclic ring is unsubstituted or replaced by one, two or three remains chosen independently each other between lower alkyl, lower alkoxy and oxo, or is condensed with a phenyl ring, said phenyl ring is without replace or substituted by one, two or three remains chosen with independence from each other between lower alkyl, lower alkoxy and halogen;

TO

choose between

5

in the that

m

it is 0, 1 or 2;

n

it is 0, 1 or 2;

R 3

it is hydrogen or lower alkyl;

t

it is 1 or 2;

R 4

it is hydrogen or lower alkyl;

X

it is O, S or N-R 8; R8 being hydrogen or lower alkyl;

p

it is 0, 1 or 2;

R 5

it is lower alkyl;

that

it is 0, 1 or 2;

R 6

it is lower alkyl;

s

it is 0, 1 or 2;

R 7

it is lower alkyl;

and pharmaceutically salts acceptable of same.

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Preferred compounds of the formula I of the The present invention are compounds of the formula I, in which R1 is selected from the group consisting of hydrogen, alkyl lower, unsubstituted phenyl or substituted by one or two moieties independently chosen from each other among lower alkyl, lower halogenoalkoxy or lower hydroxyalkyl and phenyl-lower alkyl in which the phenyl ring it can be unsubstituted or substituted by one or two residues independently chosen from each other among lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and R2 is hydrogen or lower alkyl.

Especially preferred are the compounds of the formula I, wherein R 1 is phenyl alkyl bottom in which the phenyl ring may be unsubstituted or replaced by one or two remains independently selected from each other between lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower and R2 is hydrogen or lower alkyl.

Also preferred are the compounds of the formula I of the present invention, wherein R2 is chosen between the group formed by

quad

hydrogen, lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl,

quad

(lower alkoxy) alkyl, (alkyl lower) sulfanylalkyl, di (alkyl lower) aminoalkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

pyrrolidinyl unsubstituted or substituted by a residue chosen from lower alkyl or halogen,

quad

lower heteroarylalkyl, in which the ring heteroaryl is unsubstituted or substituted by one or two moieties lower alkyl, and

quad

lower heterocyclyl alkyl, in which the ring heterocyclic is unsubstituted or substituted by one or two moieties lower alkyl.

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Especially preferred are those compounds of the formula I, in which R2 is chosen from the group formed by

quad

hydrogen,

quad

lower alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower,

quad

phenyl-lower alkyl, in which the phenyl ring is unsubstituted or substituted by one or two moieties independently chosen from each other among the group formed by lower alkyl, halogen, lower alkoxy and hydroxyalkyl lower and

quad

pyrrolidinyl unsubstituted or substituted by a residue chosen from lower alkyl and halogen.

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Another group of preferred compounds of the formula I according to the invention is formed by those, in which R1 and R2 together with the nitrogen atom to which they are together they form a heterocyclic ring of 4, 5, 6 or 7 links, saturated or partially unsaturated, which optionally contains another heteroatom chosen from nitrogen, oxygen and sulfur, said ring saturated heterocyclic is unsubstituted or substituted by one, two or three remains chosen independently from each other among the group formed by lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl and (lower halogenoalkyl) carbonylamino, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or replaced by one, two or three remains chosen independently each other between lower alkyl, lower alkoxy and halogen.

Especially preferred are those compounds of the formula I, in which R 1 and R 2 together with the atom of nitrogen to which they are attached form a heterocyclic ring chosen between the group formed by piperidine, piperazine, pyrrolidine, thiomorpholine, morpholine and azepane, said heterocyclic ring is unsubstituted or substituted by one, two or three remains chosen with independence from each other between the group formed by lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, alkoxy lower, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl and (halogenoalkyl lower) carbonylamino, or is condensed with a ring phenyl, said phenyl ring is unsubstituted or substituted by one, two or three remains independently selected from each other among alkyl lower, lower alkoxy and halogen.

Other preferred compounds of formula I are those, in which R1 and R2 together with the atom of nitrogen to which they are attached form a heterocyclic ring 5 or 6 link saturated optionally containing another heteroatom chosen from nitrogen, oxygen and sulfur, said ring saturated heterocyclic is unsubstituted or substituted by one, two or three remains chosen independently from each other among alkyl lower, lower alkoxy and oxo, or is condensed with a ring phenyl, said phenyl ring is unsubstituted or substituted by one, two or three remains independently selected from each other lower alkyl, lower alkoxy and halogen.

Within this group, those are preferred. compounds of the formula I, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a ring heterocyclic chosen from the group formed by piperidine, piperazine, pyrrolidine, thiomorpholine and morpholine, said ring heterocyclic is unsubstituted or substituted by one, two or three remains chosen independently of each other from lower alkyl, lower alkoxy and oxo, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or substituted by one, two or three remains chosen independently of each other from lower alkyl, lower alkoxy and halogen.

Even more preferably, R1 and R2 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring, chosen from the group consisting of the piperidine, piperazine, pyrrolidine and 3,4-dihydro-1H-isoquinoline, in which the ring is unsubstituted or substituted by alkyl lower.

Other preferred compounds of formula I according to the present invention are those, in which A means

6

in which m is 0, 1 or 2; n is 0, 1 or 2; R 3 is hydrogen or lower alkyl and R 9 and R 10 independently of each other they choose between hydrogen and alkyl lower.

Especially preferred are those compounds, in which R 9 and R 10 are hydrogen, i.e. compounds of the formula I, in which A means

7

in which m is 0, 1 or 2; n is 0, 1 or 2; and R 3 is hydrogen or alkyl lower.

Within this group are preferred compounds of the formula I, in which m is 1 and n is 1, meaning thus, piperidine moieties are preferred.

Another preferred group of compounds is the formed by those compounds of the formula I, in which A means

8

in which m is 0, 1 or 2; t is 1 or 2; R 4 is hydrogen or lower alkyl; and X is O, S or N-R 8; R8 being hydrogen or alkyl lower; being more preferred those compounds, in which t is 1 and X is O, that is morpholine derivatives, being even more preferred those compounds, in which m is one.

In addition, compounds of formula I according to the invention, in which A means

9

where p is 0, 1 or 2 and R 5 is lower alkyl or cycloalkyl

Especially preferred are those compounds of formula I, wherein R 5 is lower alkyl.

Within this group they are especially preferred compounds of the formula I, in which p is 0 or in the that p is 1, meaning that they are especially preferred the pyrrolidine or piperidine residues.

Compounds of the formula I according to the present invention, in which A means

10

in which q is 0, 1 or 2; and R 6 it's alkyl lower.

Within this group are preferred compounds of the formula I, in which q is 0. This means that they are  preferred pyrrolidine moieties.

Also preferred are those compounds of the formula I, in which q is 1, this means that they are also preferred piperidine moieties.

Another group of preferred compounds is the formed by the compounds of the formula I, in which A it means

eleven

in which s is 0, 1 or 2; and R 7 it's alkyl lower.

Especially preferred are the compounds of formula I, in which s is 1. the moieties are therefore preferred piperidine

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Examples of preferred compounds of the Formula I are as follows:

piperidin-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone;

(4-methyl-piperidin-1-yl) - {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-Isopropyl-piperazin-1-yl) - {6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

(2-methyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} - (2-methyl-pyrrolidin-1-yl) -methanone,

{6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} - (2-methyl-pyrrolidin-1-yl) -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - {6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

benzyl methyl amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

benzyl methyl amide of the acid 6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalene-2-carboxylic acid,

[6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

[6- (3-morpholin-4-yl-propoxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -thiomorpholin-4-yl-methanone,

{6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -thiomorpholin-4-yl-methanone,

(4-methoxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-methoxy-piperidin-1-yl) - {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -methanone,

(4-methoxy-piperidin-1-yl) - {6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

3-methoxy-benzylamide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

3-methoxy-benzylamide of the acid 6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalene-2-carboxylic acid,

morpholin-4-yl- [6- (3-morpholin-4-yl-propoxy) -naphthalen-2-yl] -methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -morpholin-4-yl-methanone,

{6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -morpholin-4-yl-methanone,

[6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone,

{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -piperidin-1-yl-methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -piperidin-1-yl-methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] -piperidin-1-yl-methanone,

(4-methyl-piperidin-1-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone,

(2-methyl-pyrrolidin-1-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] - (2-methyl-pyrrolidin-1-yl) -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-methyl-pyrrolidin-1-yl) -methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-methyl-pyrrolidin-1-yl) -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-methyl-piperidin-3-ylmethoxy) -naphthalen-2-yl] -methanone,

benzyl methyl amide of the acid 6- [2- (1-Methyl-pyrrolidin-2-yl) -ethoxy] -naphthalene-2-carboxylic acid,

benzyl methyl amide of the acid 6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalene-2-carboxylic acid,

benzyl methyl amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

benzyl methyl amide of the acid 6- (1-Isobutyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -thiomorpholin-4-yl-methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

(4-methoxy-piperidin-1-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] - (4-methoxy-piperidin-1-yl) -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methoxy-piperidin-1-yl) -methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methoxy-piperidin-1-yl) -methanone,

3-methoxy-benzylamide of the acid 6- [2- (1-Methyl-pyrrolidin-2-yl) -ethoxy] -naphthalene-2-carboxylic acid,

3-methoxy-benzylamide of the acid 6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalene-2-carboxylic acid,

3-methoxy-benzylamide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

3-methoxy-benzylamide of the acid 6- (1-Isobutyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

3-methoxy-benzylamide of the acid 6- (1-methyl-piperidin-3-ylmethoxy) -naphthalene-2-carboxylic acid,

{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -morpholin-4-yl-methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

1: 1 hydrochloride [6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone,

[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

(4-Isopropyl-piperazin-1-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-isopropyl-piperazin-1-yl) -methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (1-methyl-piperidin-3-ylmethoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -piperidin-1-yl-methanone,

1: 1 hydrochloride (1,1-dioxo-6-thiomorpholin-4-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

[6- (2,2-Dimethyl-3-piperidin-1-yl-propoxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone,

1: 1 acid ethylamide hydrochloride 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl methyl amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (4,4-difluor-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (2,6-dimethyl-morpholin-4-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride methyl phenethyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 acid propylamide hydrochloride 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid methylpropylamide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl propyl amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid cyclohexyl methyl amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-hydroxy-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride benzyl isopropyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 acid butylamide hydrochloride 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride azetidin-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride azepan-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride ethyl- (2-methoxy-ethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid cyclopropylmethyl amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl isopropyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride bis- (2-methoxy-ethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-methoxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4-hydroxymethyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride isobutyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid cyclohexyl ethyl amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 cyclopropylamide hydrochloride acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (2-methoxy-ethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [2- (3,4-Dimethoxy-phenyl) -ethyl] -methyl-amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl- (2-fluor-benzyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (2-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride (4-benzyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (3-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride ethyl-pyridin-4-ylmethyl-amide  of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 acid cyclobutylamide hydrochloride 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (4-phenyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (2-thiophen-2-yl-ethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-methoxy-propyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-methyl-thiophene-2-ylmethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride [2- (2-methyl-piperidin-1-yl) -ethyl] -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (1,3-dihydro-isoindol-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride (2-morpholin-4-yl-ethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (thiophen-2-ylmethyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3,6-dihydro-2H-pyridin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] - (3-pyridin-2-yl-pyrrolidin-1-yl) -methanone,

1: 2 hydrochloride (2-dimethylamino-ethyl) -ethyl-amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (4-fluor-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4-benzyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride (4-methyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 cycloheptylamide hydrochloride acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 cyclopentylamide hydrochloride acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (4-hydroxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 acid amide hydrochloride 1- [6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carbonyl] -piperidine-4-carboxylic acid,

1: 1 hydrochloride (3-hydroxymethyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 acid cyclohexylamide hydrochloride 6- (3-piperidin-1-yl-propoxy) -naphthalene-2-carboxylic;

1: 1 hydrochloride (4-bromo-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4-Benzyl-4-hydroxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride [3- (1-hydroxy-ethyl) -phenyl] -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-methanesulfonyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (2-Isopropyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (3,4-dimethyl-phenyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (3-dimethylamino-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 2,2,2-Trifluor-N- {1- [6- (3-piperidin-1-yl-propoxy) -naphthalene-2-carbonyl] -pyrrolidin-3-yl} -aceta- hydrochloride
measure,

1: 2 hydrochloride methyl- (1-methyl-pyrrolidin-3-yl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] - (4-trifluoromethyl-piperidin-1-yl) -methanone,

1: 2 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methyl-piperazin-1-yl) -methanone,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-isopropyl-pyrrolidin-1-yl) -methanone,

1: 1 hydrochloride (4-benzyl-piperidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride (4-isopropyl-piperazin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4-hydroxymethyl-piperidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (2-methoxy-ethyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride Acid 4-methyl-benzylamide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-trifluoromethyl-piperidin-1-yl) -methanone,

1: 1 hydrochloride (4-fluor-piperidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4,4-difluor-piperidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride acid cyclopropylmethyl amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (2-Methylsulfanyl-ethyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride 4-Fluoro-benzylamide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (3-methoxy-piperidin-1-yl) -methanone,

1: 1 hydrochloride Phenethyl Acid Amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-hydroxy-pyrrolidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (4-hydroxy-piperidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride (3-dimethylamino-propyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl- (2-methoxy-ethyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (2-morpholin-4-yl-ethyl) amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (2-piperidin-1-yl-ethyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (4-benzyl-piperazin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride acid isopropyl methyl amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride azepan-1-yl- [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride isobutyl acid amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid cyclohexyl methyl amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl-pyridin-4-ylmethyl-amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride methyl phenethyl acid amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid methylpropylamide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride cyclopropylmethyl-propyl amide of acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (3-methoxy-propyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 acid propylamide hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 cyclopentylamide hydrochloride acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 acid cyclohexylamide hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride ethyl methyl amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride acid tert-butylamide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 cyclopropylamide hydrochloride acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 acid isopropylamide hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 acid diethylamide hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride methyl- (2-pyridin-2-yl-ethyl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride benzyl ethyl acid amide 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-methyl-piperidin-1-yl) -methanone,

1: 2 hydrochloride (3-dimethylamino-pyrrolidin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride methyl- (1-methyl-pyrrolidin-3-yl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (3-methanesulfonyl-pyrrolidin-1-yl) -methanone,

1: 1 acid cycloheptylamide hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride 2,2,2-trifluor-N- {1- [6- (1-isopropyl-piperidin-4-yloxy) -naphthalene-2-carbonyl] -pyrrolidin-3-yl} -acetamide,

1: 1 acid amide hydrochloride 1- [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carbonyl] -piperidine-4-carboxylic acid,

1: 2 hydrochloride (4-cyclopentyl-piperazin-1-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - ((R) -2-methyl-pyrrolidin-1-yl) -methanone,

[6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

and pharmaceutically salts acceptable of same.

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With special preference, the compounds of the Formula I of the present invention are as follows:

piperidin-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-Isopropyl-piperazin-1-yl) - {6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

(2-methyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -methanone,

[6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

(4-methoxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

[6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-methyl-pyrrolidin-1-yl) -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone,

benzyl methyl amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone,

3-methoxy-benzylamide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -methanone,

[6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-isopropyl-piperazin-1-yl) -methanone,

[6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -piperidin-1-yl-methanone,

1: 1 hydrochloride methyl phenethyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride benzyl isopropyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride azepan-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride ethyl- (2-fluor-benzyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 2 hydrochloride (2-dimethylamino-ethyl) -ethyl-amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride (4-benzyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 1 hydrochloride (2-Isopropyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

1: 2 hydrochloride methyl- (1-methyl-pyrrolidin-3-yl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid,

1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone,

[6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone,

and pharmaceutically salts acceptable of same.

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The following are especially preferred compounds of the formula I of the present invention:

(4-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(4-Isopropyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

(3,4-dihydro-1H-isoquinolin-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone,

[6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone,

{6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone    and pharmaceutically acceptable salts thereof.

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In addition, the pharmaceutically acceptable of the compounds of formula I and pharmaceutically esters acceptable compounds of the formula I constitute individual preferred embodiments of the present invention.

The compounds of the formula I can form addition salts with acids, for example conventional acids pharmaceutically acceptable, for example hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulfate, pyruvate, citrate, lactate, mandelate, tartrate and methanesulfonate. They are Preferred hydrochloride salts. They are also part of the present invention the solvates and hydrates of compounds of the Formula I and its salts.

The compounds of the formula I may have one or several asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers as they are by for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The forms optically active can be obtained for example by resolution of racemates, by asymmetric synthesis or by chromatography asymmetric (chromatography with an adsorbent or eluent chiral). The invention encompasses all these forms.

It will be appreciated, that the compounds of the general formula I of this invention can be derivatized into the functional groups to provide derivatives that " in vivo " are capable of converting back into the original compound. Physiologically acceptable and metabolically labile derivatives, which " in vivo " are capable of producing the original compounds of the general formula I are also contemplated within the scope of this invention.

Another aspect of the present invention is the process for obtaining the compounds of formula I already defined previously, said process consists of:

a) reacting a compound of the formula II

12

in which R1 and R2 have defined meanings previously,

with an alcohol of formula III

IIIHO-A

in which A has the meaning defined above, in the presence of a trialkylphosphine or triphenylphosphine and a diazo compound to obtain a compound of the formula I

13

and yes want,

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convert the compound obtained into a salt of pharmaceutically acceptable acid addition or, as alternative,

b) react the compound of the formula VII

14

in which A has the meaning definite previously,

with an amine of the formula V

VH-NR 1 R 2

in which R1 and R2 have the meanings defined above, under basic conditions to obtain a compound of the formula I

fifteen

and yes want,

convert the compound obtained in a pharmaceutically acid addition salt acceptable.

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In more detail, the compounds of the formula I can be obtained by the methods described below, by the methods described in the examples or by methods Similar. The appropriate conditions for each reaction step Individuals are already known to persons skilled in the art. The starting materials are commercial products or they can obtained by methods similar to those described below, to the methods described in the references cited in the text or in the examples, or by methods already known in the art.

Obtaining the compounds of the formula I of the present invention can be carried out by synthetic routes sequential or convergent. The syntheses of the invention are presented in the following scheme. The techniques required to carry out the reaction and purification of the products The results are already known to those skilled in the art. The substituents and indices used in the following description of the processes have the meaning defined above, unless otherwise indicated.

Scheme one

16

The compounds of the general formula I can Obtained according to scheme 1 as follows:

a) The reaction of carboxylic acids with the amines have been subject to extensive descriptions in the technical bibliography and subject matter experts know these procedures (as for the reaction conditions described in the technical literature concerning these reactions, see For example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999). Acid 6-hydroxy-2-naphthoic IV can conveniently transform into the amide corresponding by reaction with an amine V (which is a product commercial or accessible by the methods described in the references or by methods already known in the art; if applicable) resorting to the use of the appropriate reagents. For example, for effecting said transformation can also be used reagents of type N, N'-carbonyldiimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), hydrochloride the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide  (EDCI), 3-oxide hexafluorphosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium (HEY YOU), 1-hydroxy-1,2,3-benzotriazole (HOBT), tetrafluorborate O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium (TBTU) and the like. We have considered it convenient to carry out the reaction in a solvent of the dimethylformamide type (DMF) and in presence of a base. There is no particular restriction in as regards the nature of the solvent to be used, in the event that does not adversely affect the reaction or reagents employees and that can dissolve reagents, at least in certain measure. Examples of suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF and the like. Do not there is a particular restriction regarding the nature of the base used at this stage and in this case it can be used also any base commonly used in this type of reaction. Examples of such bases include triethylamine, the diisopropylethylamine and the like. The reaction can take place within a wide range of temperatures and the precise temperature reaction is not critical in the invention. We consider it convenient carry out the reaction by heating from the temperature ambient to reflux. The time required for the reaction it can also vary within a wide range, depending on many factors, for example the reaction temperature and the nature of reagents However, it is usually enough. a period of 0.5 h to several days, obtaining the amide derivatives II.

b) The synthesis of the ethers are described with detail in the technical literature and subject matter experts already They know these procedures (regarding the conditions of reaction described in the technical literature and related to these reactions, see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999). The transformation can be carried out by applying reaction conditions that are usually used in the call "Mitsunobu reaction", which is known to all experts in the field and has been described in detail (Hughes, David L., The Mitsunobu reaction; Organic Reactions (New York) (1992), 42, 335-656.) We consider it convenient to carry out the reaction of amide II with alcohols III (which are products commercial or are accessible by methods described in the references or by methods already known in the art; according convenient) under the conditions under which a phosphine is used, for example a trialkylphosphine, such as tributylphosphine ((n-Bu) 3 P), triphenylphosphine (Ph3P) and the like and a diazo compound, for example the diethyl azodicarboxylate (DEAD), azodicarboxylate diisopropyl (DIAD) (optionally fixed on a polymer), the tetramethyl-azodicarboxamide and the like in a solvent commonly used in these types of transformations, for example tetrahydrofuran (THF), toluene, dichloromethane and the like There is no particular restriction on the nature of the solvent to be used, in the event that it does not have negative effects on the reaction or reagents used and which can dissolve the reagents, at least to some extent. The reaction can take place over a wide range of temperatures and the Exact reaction temperature is not critical in the invention. We consider it convenient to carry out the reaction by heating from room temperature to reflux. The time required for the reaction it can also vary within a wide range, in function of many factors, namely the reaction temperature and the nature of reagents However usually it is enough a period of 0.5 h to several days to get the desired compounds of the formula I.

Alternatively, the sequence can be reversed. of the reaction steps according to scheme 2. First of all reacts alcohol III with ester VI under the conditions of a Mitsunobu reaction and then the ester decomposes. TO then the acid formed is reacted intermediate with an IV amine to carry compound I. Reagents and Ideal conditions are described in the previous step a).

Scheme 2

17

As described above, the compounds of the formula I of the present invention may be used as medicines for the treatment and / or prevention of diseases associated with modulation of H3 receptors. They are examples of such diseases obesity, metabolic syndrome (syndrome X), neurological diseases, including disease Alzheimer's disease, dementia, related memory dysfunction with age, mild cognitive imbalance, cognitive deficit, attention deficit hyperactivity disorder, the epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, vertigo, schizophrenia, depression, addiction, nausea and  sleep disorders, including narcolepsy and other diseases, including asthma, allergy, responses of airways induced by allergy, congestion, chronic obstructive pulmonary disease and disorders gastrointestinal It is preferred to use it as a medicine for treatment and / or prevention of obesity.

The invention thus also relates to pharmaceutical compositions containing an already defined compound above and a pharmaceutically excipient and / or adjuvant acceptable.

In addition, the invention relates to compounds and defined above, intended for substance use therapeutically active, particularly substances Therapeutically active for the treatment and / or prevention of diseases associated with modulation of H3 receptors. They are examples of such diseases obesity, metabolic syndrome (syndrome X), neurological diseases, including disease Alzheimer's, dementia, memory dysfunction related to age, mild cognitive imbalance, cognitive deficit disorder attention deficit hyperactivity, epilepsy, pain neuropathic, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, vertigo, schizophrenia, depression, addiction, nausea and sleep disorders, including narcolepsy and other diseases including asthma, allergy, pathway responses respiratory allergy, congestion, disease Chronic obstructive pulmonary and gastrointestinal disorders.

The compounds of the invention can be used in a method for the treatment and / or prevention of diseases associated with modulation of H3 receptors. They are examples of such obesity diseases, metabolic syndrome (syndrome X), neurological diseases, including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive imbalance, cognitive deficit disorder attention deficit hyperactivity, epilepsy, pain neuropathic, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, vertigo, schizophrenia, depression, addiction, nausea and sleep disorders, including narcolepsy and other diseases including asthma, allergy, pathway responses respiratory allergy, congestion, disease Chronic obstructive pulmonary and gastrointestinal disorders. Is preferred a method for the treatment and / or prevention of obesity.

The invention further relates to the use of compounds of the formula I already defined above for the treatment and / or prevention of diseases associated with the H3 receptor modulation. Examples of such diseases are obesity, metabolic syndrome (syndrome X), diseases neurological, including Alzheimer's disease, dementia, age-related memory dysfunction, imbalance mild cognitive, cognitive deficit, hyperactivity disorder attention deficit, epilepsy, neuropathic pain, pain inflammatory, migraine, Parkinson's disease, sclerosis multiple, stroke, vertigo, schizophrenia, depression, addiction, nausea and sleep disorders, including narcolepsy and others diseases, including asthma, allergy, pathway responses respiratory allergy, congestion, disease Chronic obstructive pulmonary and gastrointestinal disorders. Is preferred the use of the compounds of the formula I already defined previously for the treatment and / or prevention of obesity.

In addition, the invention relates to the use of compounds of the formula I already defined above for the manufacture of medicines intended for treatment and / or prevention of diseases associated with H3 receptor modulation. They are examples of such diseases obesity, metabolic syndrome (syndrome X), neurological diseases, including disease Alzheimer's, dementia, memory dysfunction related to age, mild cognitive imbalance, cognitive deficit disorder attention deficit hyperactivity, epilepsy, pain neuropathic, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, vertigo, schizophrenia, depression, addiction, nausea and sleep disorders, including narcolepsy and other diseases, including asthma, allergy, responses of airways induced by allergy, congestion, disease Chronic obstructive pulmonary and gastrointestinal disorders. Is preferred the use of the compounds of the formula I already defined previously for the manufacture of medicines intended for treatment and / or prevention of obesity.

The compounds of formula I and their salts Pharmaceutically acceptable possess pharmacological properties valuable. It has been specifically found that the compounds of the present invention are good antagonists and / or agonists inverse of histamine 3 receptors (H3R).

The following test is carried out in order of determining the activity of the compounds of the formula (I).

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Fixation test with the (R) α-methylhistamine-H 3

Saturation fixation assays are carried out using HR3-CHO membranes prepared in the manner described by Takahashi, K., Tokita, S., Kotani, H., J. Pharmacol. Exp. Therapeutics 307 , 213-218, 2003.

An appropriate amount of membrane is incubated (of 60 to 80 µg of protein / hole) with increasing concentrations of dihydrochloride (R) α-methylhistamine-H 3 (from 0.10 to 10 nM). No specific fixation is determined when 200 greater excess of dibromhydrate than (R) cold α-methylhistamine (final concentration: 500 nM). Incubation is carried out at room temperature (in deep hole plates, stirring for three hours). The final volume of each hole is 250 µl. After incubation a rapid filtration is performed in GF / B filters (preimpregnated with 100 µl of 0.5% PEI in buffer 50 mM Tris stirring at a speed of 200 rpm for two hours). Filtration is done using a cell collector and the filter plates are then washed five times with a buffer of ice-cold wash, containing 0.5 M NaCl. After collection the plates are dried at 55 ° C for 60 min, then add scintillation fluid (Microscint 40, 40 microliters to each hole) and the amount of radioactivity in the filter is determined in a top-counter Packard device after stirred the plates for two hours at 200 rpm at temperature ambient.

Fixing buffer: 50 mM Tris-HCl, pH 7.4, and 5 mM MgCl 2 x 6 H 2 O, pH 7.4. Wash buffer: 50 mM Tris-HCl, pH 7.4, and 5 mM MgCl 2 x 6 H 2 O and 0.5 M NaCl, pH 7.4.

Indirect measurement of the affinity of inverse agonists of the H3R: twelve are always tested increasing concentrations (between 10 µM and 0.3 nM) of the compounds selected in competition fixation tests using a human cell line membrane HR3-CHO. An appropriate amount of protein, eg approximately 500 cpm of RAMH binding in Kd, for 1 hour at room temperature in a final volume of 250 \ mul in 96-hole plates in the presence of (R) α-methylhistamine-H 3 (final concentration 1 nM = Kd). Fixation is determined not specific using 200 times greater excess of dibromhydrate (R) cold α-methylhistamine.

All compounds are tested in duplicate in a single concentration. Compounds that exhibit an inhibition of RAMH- [H 3] greater than 50% are retested to determine the IC 50 in a serial dilution test. Ki values are calculated from IC50s based on the Cheng-Prusoff equation (Cheng, Y., Prusoff, WH, Biochem. Pharmacol. 22 , 3099-3108, 1973).

The compounds of the present invention have K_ {i} values within a range between 1 nM and 1000 nM, preferably between 1 nM and 100 nM and with greater preference between 1 nM and 30 nM. The following table shows the measured values for some compounds selected from the present invention

18

The compounds of the formula (I) and their salts and Pharmaceutically acceptable esters can be used as medicines, eg in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, eg in the form of tablets, tablets coated, dragee, hard and soft gelatin capsules, solutions, emulsions or suspensions; rectally, eg in form of suppositories, parenterally, eg in the form of injectable solutions or infusion solutions, or via topical, eg in the form of ointments, creams or oils.

The production of pharmaceutical preparations it can be done in a way that will be familiar to any expert in the matter incorporating the described compounds of the formula (I) and its pharmaceutically acceptable salts, in a form of Galenic administration together with solid excipient materials or suitable, non-toxic, inert, therapeutically compatible liquids and, if desired, the usual pharmaceutical adjuvants.

Suitable excipient materials are inorganic excipient materials and also excipient materials organic For example, as excipient materials for tablets, coated tablets, dragees and hard gelatin capsules lactose, corn starch or derivatives thereof may be used, talc, stearic acid or its salts. Excipient materials suitable for soft gelatin capsules are, for example, the vegetable oils, waxes, fats and semi-solid polyols and liquids (however, depending on the nature of the principle It is possible to dispense with the excipient in the case of soft gelatin capsules). The ideal excipient materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. The materials excipients suitable for solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. The materials excipients suitable for suppositories are, for example, the natural and hydrogenated oils, waxes, fats and semi-liquid and liquid polyols. The ideal excipient materials for topical preparations are glycerides, glycerides semi-synthetic and synthetic, hydrogenated oils, waxes liquids, liquid paraffins, liquid fatty acids, sterols, polyethylene glycols and cellulose derivatives.

As pharmaceutical adjuvants are taken in consideration of the usual stabilizers, preservatives, agents humectants and emulsifiers, agents that confer consistency, flavor enhancing agents, salts to vary the pressure osmotic, buffer substances, solubilizers, dyes and agents masks and antioxidants.

The dosage of the compounds of the formula (I) may vary within wide limits depending on the disease to be controlled, age and health status of the individual patient and administration mode and obviously It must conform to the peculiarities of the individual in each case. For adult patients a dosage is considered daily from 1 mg to 1000 mg, especially 1 mg to 100 mg. Function of the daily dose, it is convenient to administer it divided into several subdose

Pharmaceutical preparations contain convenient mode of 0.1 to 500 mg, preferably 0.5 to 100 mg, of a compound of the formula (I).

The following examples serve to illustrate the present invention in greater detail. However, it is not intended with them limit your reach in any way.

Examples

Intermediate product TO

(6-hydroxy-naphthalen-2-yl) -piperidin-1-yl-methanone

19

Stir at room temperature for 16 h a mixture of 0.5 g (0.003 mol) acid 6-hydroxy-2-naphthoic,  1.2 g (0.003 mol) of tetrafluorborate 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium, 2.3 ml of (0.013 mol) of N-ethyldiisopropylamine and 0.29 ml of (0.030 mol) of piperidine in 10 ml of DMF. It concentrates the mixture to dryness and 50 ml of ethyl acetate are added, 30 ml of water and 20 ml of an aqueous solution of NaHCO3 (10%). The aqueous phase is extracted with 50 ml of ethyl acetate, combined The organic phases are purified by column chromatography at through silica gel. The fractions are concentrated to dryness which contain product and are crushed twice with 20 ml of a 1/1 mixture of diethyl ether / heptane. The residue is dried under vacuum at 50 ° C, obtaining 0.58 g (0.0227 mmol; 85%) of the compound epigraph in the form of a slightly brown solid. MS (m / e): 254.3 (MH <->, 100%).

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Intermediate product B

(6-hydroxy-naphthalen-2-yl) - (4-methyl-piperidin-1-yl) -methanone

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twenty

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and 4-methyl-piperidine (product commercial) according to the procedure described in example A. EM (m / e): 268.5 (MH <->, 100%).

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Intermediate product C

(6-hydroxy-naphthalen-2-yl) - (4-isopropyl-piperazin-1-yl) -methanone

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twenty-one

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and N-Isopropyl Piperazine (product commercial) according to the procedure described in example A. EM (m / e): 299.3 (MH +, 100%).

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Intermediate product D

(6-hydroxy-naphthalen-2-yl) - (2-methyl-pyrrolidin-1-yl) -methanone

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22

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and 2-methyl-pyrrolidine (product commercial) according to the procedure described in example A. EM (m / e): 254.1 (MH -, 100%).

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Intermediate product AND

(3,4-dihydro-1H-isoquinolin-2-yl) - (6-hydroxy-naphthalen-2-yl) -methanone

2. 3

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and 1,2,3,4-tetrahydroisoquinoline (commercial product) according to the procedure described in example A. MS (m / e): 302.1 (MH <->, 100%).

Intermediate product F

Benzyl Methyl Acid Amide 6-hydroxy-naphthalene-2-carboxylic

24

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and N-methylbenzylamine (product commercial) according to the procedure described in example A. EM (m / e): 290.1 (MH -, 100%).

Intermediate product G

(6-hydroxy-naphthalen-2-yl) -thiomorpholin-4-yl-methanone

25

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and thiomorpholine (commercial product) with according to the procedure described in example A. MS (m / e): 272.0 (MH <->, 100%).

Intermediate product H

(6-hydroxy-naphthalen-2-yl) - (4-methoxy-piperidin-1-yl) -methanone

26

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and 4-methoxy-piperidine (product commercial) according to the procedure described in example A. EM (m / e): 284.0 (MH -, 100%).

Intermediate product I

Acid 3-methoxy-benzylamide 6-hydroxy-naphthalene-2-carboxylic

27

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and 3-methoxy-benzylamine (product commercial) according to the procedure described in example A. EM (m / e): 306.2 (MH -, 100%).

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Intermediate product J

(6-hydroxy-naphthalen-2-yl) -morpholin-4-yl-methanone

28

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and morpholine (commercial product) with arrangement to the procedure described in example A. MS (m / e): 256.0 (MH <->, 100%).

Intermediate product K

(6-hydroxy-naphthalen-2-yl) -pyrrolidin-1-yl-methanone

29

The epigraphy compound is synthesized from of acid 6-hydroxy-2-naphthoic (commercial product) and pyrrolidine (commercial product) with arrangement to the procedure described in example A. MS (m / e): 240.4 (MH <->, 100%).

Example 1 1: 1 hydrochloride piperidin-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone

It is stirred at room temperature for a prolonged period of time a mixture of 51 mg (0.2 mmol) of the (6-hydroxy-naphthalen-2-yl) -piperidin-1-yl-methanone, 350 mg (about 3 mmol) of polymer-fixed triphenylphosphine (Fluka), 34 mg (0.24 mmol) of piperidinepropanol and 92 mg (0.4 mmoles) of azadicarboxylate di-tert-butyl in 2 ml of THF. Be filter the mixture through a bed of silica gel and wash with 3 ml of THF. HCl in methanol (0.8 ml; 1.25 M) is added and Concentrate the mixture to dryness. The residue is taken up in methanol and  Purify by preparative reverse phase HPLC chromatography eluting with acetonitrile / water / HCl. The fractions that meet contain product and concentrate under reduced pressure, obtaining 40 mg (46%) of the foam-shaped epigraphy compound slightly brown MS (m / e): 381.3 (MH +, 100%).

In accordance with the procedure described for synthesis of example 1 other derivatives have been synthesized from of the (6-hydroxy-naphthalen-2-yl) -amine-4-yl-methanone respective and of the respective alcohol. The results are collected in Table 1 and comprise from example 1 to example 73.

TABLE 1

30

31

32

33

3. 4

35

36

37

38

39

40

41

42

43

44

Four. Five

46

47

48

49

fifty

51

52

Example 74 1: 1 hydrochloride (1,1-dioxo-6-thiomorpholin-4-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone

Stir at room temperature for 4 h a mixture of 0.12 g (0.3 mmol) of 1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone  (example 50) and 0.443 g (0.75 mmol) of potassium monopersulfate, triple salt (Oxone®), in 5 ml of methanol and filtered. It concentrates the liquid filtered by evaporation to dryness and the residue through silica gel eluting with a mixture of 92/2 a 9/1 of DCM / NH3 2N in MeOH. The fractions that are concentrated are concentrated. they contain product and the residue is collected in methanol and then It is then treated with 0.5 ml of 1.25N HCl in methanol and concentrated to dryness, obtaining 16 mg (11%) of the compound epigraph in the form of slightly yellow foam. MS (m / e): 431.4 (MH +, 100%).

Example 75 [6- (2,2-Dimethyl-3-piperidin-1-yl-propoxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone

The epigraphy compound is synthesized from from (6-hydroxy-naphthalen-2-yl) - (4-methyl-piperidin-1-yl) -methanone  (intermediate product B) and 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol (commercial product) according to the procedure described for Synthesis of Example 1. MS (m / e): 423.1 (MH +, 100%).

Intermediate product L

6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylate of methyl

53

Stir at room temperature for 16 h a mixture of 20.2 g (0.1 mol) of 6-hydroxy-naphthalene-2-carboxylate  of methyl (commercial product), 18.6 g (0.13 mol) of 1-piperidinepropanol (commercial product), 50.4 g (0.2 mol) of 1,1 '- (azodicarbonyl) dipiperidine and 58 ml (0.2 moles) of tri-n-butyl phosphine in 400 ml of THF. The suspension is filtered and the liquid is concentrated filtered to dryness. The residue is taken up in 200 ml of DCM and given add 400 g of Isolute® HM-N (Argonaut Technologies Inc., support material for accelerated extraction with solvent) and concentrated to dryness. The residue is chromatographed on through silica gel eluting with a gradient formed by a 99/1 to 9/1 mixture of DCM / MeOH (2N NH3). After the concentration the residue is treated with heptane / diethyl ether, it is Separate the precipitate by filtration and wash again with heptane / diethyl ether. It is dried at 50 ° C under reduced pressure, obtaining 25 g (76%) of the epigraphy compound in the form of white solid MS (m / e): 328.3 (MH +, 100%).

Example M 1: 1 acid hydrochloride 6- (3-piperidin-1-yl-propoxy) -naphthalene-2-carboxylic

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54

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A mixture of 24.1 g (0.074 mol) of 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylate  of methyl (intermediate L) and 3.4 g (0.081 mol) of LiOH.H2O in 250 ml of THF, 100 ml of water and 50 ml of methanol. After evaporation of the organic solvents 200 are added ml of ice / water and 50 ml of 4 N HCl. The precipitate is separated by filtration, washed with water, acetonitrile and diethyl ether and dried at 80 ° C under reduced pressure, obtaining 22.6 g (88%) of the white solid epigraphy compound. MS (m / e): 314.0 (MH +, 100%).

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Example N 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylate of methyl

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55

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In accordance with the procedure described for synthesis of 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylate  of methyl (intermediate L) the compound is synthesized epigraphied from 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylate  of methyl (commercial product) and 1-isopropyl-piperidin-4-ol (obtained according to Acta Physica et Chemica 1980, 26 (3-4), 177-184). MS (m / e): 328.3 (MH +, 100%).

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Intermediate product OR

1: 1 acid hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic

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56

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In accordance with the procedure described for 1: 1 acid hydrochloride synthesis 6- (3-piperidin-1-yl-propoxy) -naphthalene-2-carboxylic  (intermediate product M) the epigraphy compound is synthesized at start from 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylate  of methyl (intermediate N) and LiOH. MS (m / e): 314.0 (MH +, 100%).

In accordance with the procedure described for synthesis of intermediate A other derivatives are synthesized amide from 1: 1 acid hydrochloride 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic or 1: 1 acid hydrochloride 6- (3-piperidin-1-yl-propoxy) -naphthalene-2-carboxylic and the respective amines (commercial products) listed in the list in table 2. The purification is carried out by preparative HPLC chromatography on a phase column material inverse, eluting with a gradient formed by acetonitrile / water (0.02% HCl (25%)). The concentration of the fractions that contain product allows to obtain the corresponding amides, which range from example 76 to example 186 in table 2.

TABLE 2

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

Example 187 [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - ((R) -2-methyl-pyrrolidin-1-yl) -methanone

The 1: 1 hydrochloride of the (2-methyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone  racemic (example 6) on a ChiralPack AD® column (Daicel Chemical Industries Ltd.) eluting with an 85/15 heptane / ethanol mixture. Fractions containing product are concentrated, obtaining 175 mg (38%) of the desired product as a white solid. EM (m / e): 381.2 (MH +, 100%).

Example 188 [6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone

He passed one

3- [cyclopropyl- (2-ethoxycarbonyl-ethyl) -amino] -propionate of ethyl

Stir at room temperature for 24 h a mixture of ethyl acrylate (30.0 g, 300 mmol, 2.0 eq.) and cyclopropyl-amine (8.5 ml, 149 mmol, 1.0 eq.) in absolute ethanol (45 ml). The crude mixture is purified by fractional distillation under vacuum (20 mbar). A fraction is collected (boiling point: 135 ° C at 20 mbar), obtaining 20.58 g (54%) of the desired product as a colorless oil. MS (m / e): 274.3 (MH +, 100%).

He passed 2

1-cyclopropyl-piperidin-4-one

A solution of drip is added 3- [cyclopropyl- (2-ethoxycarbonyl-ethyl) -amino] -propionate ethyl (10.0 g, 39 mmol, 1.0 eq.) in anhydrous tetrahydrofuran (65 ml) to a solution of sodium hydride (60% dispersion in oil, 2.33 g, 58 mmol, 1.5 eq.) in anhydrous tetrahydrofuran (65 ml) Then, absolute ethanol (1.79 g, 39 mmol, 1.0 eq.). The resulting mixture is heated at reflux for 24 h. The solution obtained (pH: 7) is neutralized with acetic acid diluted and partitioned between water and ethyl acetate. The aqueous phase with ethyl acetate. The extracts are gathered, dried with sodium sulfate and the solvent is removed in vacuo, obtaining 10.2 g of a reddish oil.

This oil is then heated to reflux in crude with 18% w / w hydrochloric acid (130 ml) for 5 h. After basifying the crude mixture with sodium hydroxide (approx. 31 g, pH: approx. 12), extracted with ethyl acetate. They meet extracts, dried with sodium sulfate and the solvent is removed with emptiness The crude mixture is purified by distillation fractionated under vacuum (20 mbar). A fraction is collected (point of boiling: 75 ° C at 20 mbar), obtaining 3.6 g (67%) of the product desired in the form of colorless oil. MS (m / e): 140.0 (MH +, 100%)

He passed 3

1-cyclopropyl-piperidin-4-ol

To a cooled solution (0 ° C) of 1-cyclopropyl-piperidin-4-one (1.5 g, 11 mmol, 1.0 eq.) In absolute ethanol is added sodium borhydride (306 mg, 8 mmol, 0.75 eq.). The mixture is stirred reactant at room temperature for 65 h. The mix with vacuum. Water ice is added (10 ml) and then an aqueous solution of sodium hydroxide (28% w / w, approx. 10 ml) and dichloromethane (20 ml). The mixture is stirred at temperature ambient for 2 h. After phase separation, it Extract the aqueous phase with dichloromethane. The phases meet organic, washed with brine, dried with sodium sulfate, dried filter and concentrate by evaporation under vacuum. The raw mixture through silica gel, eluting with a mixture 93/7 of DCM / NH3 2N in methanol, thus 1.44 g are obtained (95%) of the desired product as a colorless oil. MS (m / e): 423.1 (MH +, 100%).

He passed 4

6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylate of methyl, hydrochloric acid salt

To a solution of 1-cyclopropyl-piperidin-4-ol (272 mg, 1.9 mmol, 1.3 eq.) In tetrahydrofuran (7 ml) is given add a solution of 6-hydroxy-naphthalene-2-carboxylate of methyl (commercial product) (300 mg, 1.48 mmol, 1.0 eq.) in tetrahydrofuran (5 ml) and tri-n-butylphosphine (600 mg, 2.96 mmoles, 2 eq.). In 3 min a solution of azodicarbonyldipiperidine (749 mg, 2.97 mmol, 2.0 eq.) in tetrahydrofuran (5 ml). The reaction mixture is stirred at room temperature for 48 h. The mixture is concentrated. Reactant under vacuum, stir in 15 ml of a 1/1 v / v mixture of dichloromethane / heptane and filtered. The solid is washed with 15 ml of dichloromethane / heptane and then discarded. The waters are concentrated Mothers with emptiness. The crude mixture is dissolved in acetate ethyl (10 ml). A solution of hydrochloric acid in acetate is added of ethyl (2.23 M, 4 ml) and then ether of methyl tert-butyl (10 ml). It shakes the resulting mixture at 0 ° C for 2 h and then filtered. Wash the solid with ether of methyl tert-butyl and then dried under vacuum, obtaining 240 mg (45%) of the desired product in the form of white solid. MS (m / e): 362.7 (MH +, 100%).

He passed 5

[6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone

To a solution of 6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylate of methyl, hydrochloric acid salt (205 mg, 0.57 mmol, 1.0 eq.) in a mixture of tetrahydrofuran (3 mL), methanol (1.5 ml) and water (1 ml) lithium hydroxide (52 mg, 1.25 mmol, 2.2 eq.) is added. The mixture is stirred at 45 ° C overnight. The mixture is concentrated. raw with vacuum. Water (2 ml) is added and the suspension (pH approx. 2) with hydrochloric acid. The solution with vacuum.

This crude mixture is dissolved with dimethylformamide (5 ml). Tetrafluorborate from O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium,  morpholine and diethylisopropylamine. The crude mixture is stirred at room temperature for 24 h. The mixture is divided between ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase is extracted with acetate ethyl, the organic phases are combined and concentrated in vacuo. Be Purify the crude mixture through silica gel eluting with a 97/3 mixture of DCM / NH3 2N in methanol, yielding 145 mg (67%) of the desired product as a white solid. MS (m / e): 381.5 (MH +, 100%).

Example A

Coated tablets can be manufactured with a film containing the following ingredients by one method conventional.

1000

The active ingredient is screened and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and it compresses, obtaining cores of 120 and 350 mg, respectively. Be varnish the cores with an aqueous solution / suspension of the film type cover mentioned before.

Example B

Capsules containing the following ingredients by a conventional method.

1010

The components are screened, mixed and mixed. packed in capsules of size 2.

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Example C

Injectable solutions may have the following composition:

1020

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Example D

Soft gelatin capsules can be manufactured containing the following ingredients by one method conventional:

1030

The active ingredient is dissolved in the dough melted and hot from the other ingredients and the mixture is packaged in soft gelatin capsules of the appropriate size. The capsules of Stuffed soft gelatin are treated according to the procedures usual.

Example E

Sachets are made containing the following ingredients by a conventional method:

1040

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and it granulate with a mixture of polyvinylpyrrolidone and water. The granulated with magnesium stearate, additives are added Flavoring and packed in sachets.

Claims (33)

1. Compounds of the general formula

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99

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in the that

R1

you choose between the group formed by hydrogen,

quad

C 1 -C 8 alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by C 1 -C 8 alkyl, halogenoalkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8} ,,

quad

phenyl-alkyl C 1 -C 8, in which the phenyl ring is without replace or substituted by one or two remains chosen with independence from each other between the group formed by alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8}, and

quad

(alkoxy C 1 -C 8) alkyl;

R2

you choose between the group formed by hydrogen,

quad

C 1 -C 8 alkyl,

quad

cycloalkyl C 3 -C 7,

quad

cycloalkylalkyl C_ {1} -C_ {8},

quad

hydroxyalkyl C_ {1} -C_ {8},

quad

(alkoxy C 1 -C 8) alkyl,

quad

(I rent C 1 -C 8) sulfanylalkyl,

quad

di (alkyl C 1 -C 8) aminoalkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by C 1 -C 8 alkyl, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8},

quad

phenyl-alkyl C 1 -C 8, in which the phenyl ring is without replace or substituted by one or two remains chosen with independence from each other between the group formed by alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8},

quad

pyrrolidinyl unsubstituted or substituted by a residue selected from C 1 -C 8 alkyl or halogen,

quad

C 1 -C 8 heteroarylalkyl, wherein the heteroaryl ring is unsubstituted or substituted by one or two C 1 -C 8 alkyl moieties, Y

quad

C 1 -C 8 heterocyclylalkyl, in which the heterocyclic ring is unsubstituted or substituted by one or two C 1 -C 8 alkyl moieties; or good

R1 and R2 together with the nitrogen atom to which they are attached form a ring heterocyclic 4, 5, 6 or 7 links, saturated or partially unsaturated optionally containing another heteroatom chosen between nitrogen, oxygen and sulfur, said heterocyclic ring saturated is unsubstituted or substituted by one, two or three remains chosen independently from each other among the group formed by C 1 -C 8 alkyl, halogen, halogenoalkyl, hydroxy, hydroxyalkyl C 1 -C 8, alkoxy C 1 -C 8, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, alkylsulfonyl C 1 -C 8 and (halogenoalkyl C 1 -C 8) -carbonylamino, or is condensed with a phenyl ring, said phenyl ring is without replace or substituted by one, two or three remains chosen with independence from each other between alkyl C 1 -C 8, alkoxy C_ {1} -C_ {8} and halogen;

TO

choose between

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100

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in the that

m

it is 0, 1 or 2;

n

it is 0, 1 or 2;

R 3

it is hydrogen or lower alkyl;

R 9 and R 10 with independence from each other are chosen from hydrogen or alkyl lower;

t

it is 1 or 2;

R 4

it's hydrogen or alkyl C 1 -C 8 r;

X

it is O, S or N-R 8; R8 being hydrogen or C 1 -C 8 alkyl;

p

it is 0, 1 or 2;

R 5

it is C 1 -C 8 alkyl or C 3 -C 7 cycloalkyl;

that

it is 0, 1 or 2;

R 6

it's alkyl C 1 -C 8;

s

it is 0, 1 or 2;

R 7

it's alkyl C 1 -C 8;

and pharmaceutically salts acceptable of same.

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2. Compounds of formula I according to claim 1, wherein

R1

you choose between the group formed by

quad

hydrogen,

quad

C 1 -C 8 alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently of each other among alkyl C 1 -C 8, halogenoalkoxy C 1 -C 8 or hydroxyalkyl C_ {1} -C_ {8}, and

quad

phenyl-alkyl C 1 -C 8 in which the phenyl ring can be unsubstituted or substituted by one or two remains chosen with independence from each other between alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 or hydroxyalkyl C 1 -C 8;

R2

you choose between the group formed by

quad

hydrogen,

quad

C 1 -C 8 alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently of each other among alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 or hydroxyalkyl C_ {1} -C_ {8}, and

quad

phenyl-alkyl C 1 -C 8 in which the phenyl ring can be unsubstituted or substituted by one or two remains chosen with independence from each other between alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 or hydroxyalkyl C 1 -C 8; or

R1 and R2 together with the nitrogen atom to which they are attached form a ring 5 or 6-link saturated heterocyclic containing optionally another heteroatom chosen from nitrogen, oxygen and sulfur, said saturated heterocyclic ring is unsubstituted or replaced by one, two or three remains chosen independently each other between C 1 -C 8 alkyl, alkoxy C_ {1} -C_ {{}} and oxo, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or substituted by one, two or three remains chosen independently of each other between C 1 -C 8 alkyl, alkoxy C_ {1} -C_ {8} and halogen;

TO

choose between

101 in the that

m

it is 0, 1 or 2;

n

it is 0, 1 or 2;

R 3

it's hydrogen or alkyl C 1 -C 8;

t

it is 1 or 2;

R 4

it's hydrogen or alkyl C 1 -C 8;

X

it is O, S or N-R 8; R8 being hydrogen or C 1 -C 8 alkyl;

p

it is 0, 1 or 2;

R 5

it's alkyl C 1 -C 8;

that

it is 0, 1 or 2;

R 6

it's alkyl C 1 -C 8;

s

it is 0, 1 or 2;

R 7

it's alkyl C 1 -C 8;

and pharmaceutically salts acceptable of same.

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3. Compounds of formula I according to claims 1 or 2, wherein R1 is selected from the group formed by hydrogen, C 1 -C 8 alkyl, phenyl unsubstituted or substituted by one or two residues chosen with independence from each other between alkyl C 1 -C 8, halogenoalkoxy C 1 -C 8 or hydroxyalkyl C 1 -C 8 and phenyl-alkyl C 1 -C 8 in which the phenyl ring can be unsubstituted or substituted by one or two remains chosen with independence from each other between C1-C8 alkyl, halogen, C 1 -C 8 alkoxy or hydroxyalkyl C 1 -C 8 and R 2 is hydrogen or alkyl C_ {1} -C_ {8}. 4. Compounds of formula I according to a any one of claims 1 to 3, wherein R 1 is phenyl-C 1 -C 8 alkyl in the that the phenyl ring may be unsubstituted or substituted by one or two remains chosen independently from each other among alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 or hydroxyalkyl C_ {1} -C_ {8}.

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5. Compounds of formula I according to claim 1 or claims 3 or 4, wherein R2 is choose between the group formed by

quad

hydrogen, C 1 -C 8 alkyl, cycloalkyl, C 1 -C 8 cycloalkylalkyl, C 1 -C 8 hydroxyalkyl, (alkoxy C 1 -C 8) alkyl, (alkyl C 1 -C 8) sulfanylalkyl, di (alkyl C 1 -C 8) -aminoalkyl, phenyl unsubstituted or substituted by one or two residues chosen with independence from each other between the group formed by alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C 1 -C 8, phenyl-alkyl C 1 -C 8, in which the phenyl ring is without replace or substituted by one or two remains chosen with independence from each other between the group formed by alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C 1 -C 8, unsubstituted pyrrolidinyl or substituted by a moiety chosen from alkyl C 1 -C 8 or halogen, heteroarylalkyl C 1 -C 8, in which the heteroaryl ring is unsubstituted or substituted by one or two alkyl moieties C 1 -C 8, and heterocyclylalkyl C 1 -C 8, in which the heterocyclic ring is unsubstituted or substituted by one or two alkyl moieties C_ {1} -C_ {8}.

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6. Compounds of formula I according to claim 1 or claims 3 to 5, wherein R2 you choose between the group formed by

quad

hydrogen,

quad

C 1 -C 8 alkyl,

quad

phenyl unsubstituted or substituted by one or two remains chosen independently from each other among the group formed by C 1 -C 8 alkyl, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8},

quad

phenyl-alkyl C 1 -C 8, in which the phenyl ring is without replace or substituted by one or two remains chosen with independence from each other between the group formed by alkyl C 1 -C 8, halogen, alkoxy C 1 -C 8 and hydroxyalkyl C_ {1} -C_ {8}, and

quad

pyrrolidinyl unsubstituted or substituted by a residue selected from C 1 -C 8 alkyl or halogen

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7. Compounds of formula I according to claim 1, wherein R 1 and R 2 together with the atom of nitrogen to which they are attached form a heterocyclic ring of 4, 5, 6 or 7 links, saturated or partially unsaturated containing optionally another heteroatom chosen from nitrogen, oxygen and sulfur, said saturated heterocyclic ring is unsubstituted or replaced by one, two or three remains chosen independently each other among the group formed by alkyl C 1 -C 8, halogen, halogenoalkyl, hydroxy, C 1 -C 8 hydroxyalkyl, alkoxy C 1 -C 8, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, alkylsulfonyl C 1 -C 8 and (halogenoalkyl C 1 -C 8) carbonylamino, or is condensed with a phenyl ring, said phenyl ring is without replace or substituted by one, two or three remains chosen with independence from each other between alkyl C 1 -C 8, alkoxy C 1 -C 8 and halogen. 8. Compounds of formula I according to claims 1 or 7, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a ring heterocyclic chosen from the group formed by piperidine, piperazine, pyrrolidine, thiomorpholine, morpholine and azepane, said heterocyclic ring is unsubstituted or substituted by one, two or three remains chosen independently from each other among the group formed by C 1 -C 8 alkyl, halogen, halogenoalkyl, hydroxy, hydroxyalkyl C 1 -C 8, alkoxy C 1 -C 8, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, alkylsulfonyl C 1 -C 8 and (halogenoalkyl C 1 -C 8) carbonylamino, or is condensed with a phenyl ring, said phenyl ring is without replace or substituted by one, two or three remains chosen with independence from each other between alkyl C 1 -C 8, alkoxy C 1 -C 8 and halogen. 9. Compounds of formula I according to claims 1 or 2, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a ring 5 or 6-link saturated heterocyclic optionally containing  another heteroatom chosen from nitrogen, oxygen and sulfur, said saturated heterocyclic ring is unsubstituted or substituted by one, two or three remains independently selected from each other C 1 -C 8 alkyl, alkoxy C_ {1} -C_ {{}} and oxo, or is condensed with a phenyl ring, said phenyl ring is unsubstituted or substituted by one, two or three remains independently selected from each other among C 1 -C 8 alkyl, alkoxy C 1 -C 8 and halogen.

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10. Compounds of formula I according to claim 1 or claims 3 to 9, wherein A it means 102 in which m is 0, 1 or 2; n is 0, 1 or 2; R 3 is hydrogen or C 1 -C 8 alkyl and R 9 and R 10 independently of each other are chosen from hydrogen or alkyl C_ {1} -C_ {8}. 11. Compounds of formula I according to claim 10, wherein R 9 and R 10 are hydrogen. 12. Compounds of formula I according to claims 10 or 11, wherein m is 1 and n is 1. 13. Compounds of formula I according to a any one of claims 1 to 9, wherein A it means 103 in which m is 0, 1 or 2; t is 1 or 2; R 4 is hydrogen or C 1 -C 8 alkyl; Y X is O, S or N-R 8; R8 being hydrogen or I rent C_ {1} -C_ {8}. 14. Compounds of formula I according to claim 13, wherein t is 1 and X is O. 15. Compounds of formula I according to claim 13, wherein m is 1. 16. Compounds of formula I according to claim 1 or claims 3 to 9, wherein A it means 104 where p is 0, 1 or 2 and R 5 is C 1 -C 8 alkyl or cycloalkyl C_ {3} -C_ {7}. 17. Compounds of formula I according to claim 16, wherein R 5 is alkyl C_ {1} -C_ {8}. 18. Compounds of formula I according to claim 16, wherein p is 0. 19. Compounds of formula I according to claim 16, wherein p is 1. 20. Compounds of formula I according to a any one of claims 1 to 9, wherein A it means 105 in which q is 0, 1 or 2; and R 6 it's alkyl C_ {1} -C_ {8}. 21. Compounds of formula I according to claim 20, wherein q is 0. 22. Compounds of formula I according to claim 20, wherein q is 1. 23. Compounds of formula I according to a any one of claims 1 to 9, wherein A it means

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106

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in which s is 0, 1 or 2; and R 7 it's alkyl C_ {1} -C_ {8}. 24. Compounds of formula I according to claim 23, wherein s is 1. 25. Compounds of formula I according to claim 1, chosen from the group consisting of piperidin-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (4-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (4-Isopropyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (4-Isopropyl-piperazin-1-yl) - {6- [2- (1-methyl-piperidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone, (2-methyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (3,4-dihydro-1H-isoquinolin-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (3,4-dihydro-1H-isoquinolin-2-yl) - {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -methanone, [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone, (4-methoxy-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone, {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone, [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-methyl-piperidin-1-yl) -methanone, [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - (2-methyl-pyrrolidin-1-yl) -methanone, (3,4-dihydro-1H-isoquinolin-2-yl) - {6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone, (3,4-dihydro-1H-isoquinolin-2-yl) - [6- (1-isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -methanone, benzyl methyl amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid, [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -thiomorpholin-4-yl-methanone, 3-methoxy-benzylamide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid, [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone, (4-Isopropyl-piperazin-1-yl) - [6- (1-isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl] -methanone, [6- (1-Isobutyl-piperidin-4-yloxy) -naphthalen-2-yl] - (4-isopropyl-piperazin-1-yl) -methanone, [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -piperidin-1-yl-methanone, 1: 1 hydrochloride methyl phenethyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid, 1: 1 hydrochloride benzyl isopropyl acid amide 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid, 1: 1 hydrochloride azepan-1-yl- [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, 1: 1 hydrochloride ethyl- (2-fluor-benzyl) -amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid, 1: 2 hydrochloride (2-dimethylamino-ethyl) -ethyl-amide of the acid 6- (3-Piperidin-1-yl-propoxy) -naphthalene-2-carboxylic acid, 1: 1 hydrochloride (4-benzyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, 1: 1 hydrochloride (2-Isopropyl-pyrrolidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, 1: 2 hydrochloride methyl- (1-methyl-pyrrolidin-3-yl) -amide of the acid 6- (1-Isopropyl-piperidin-4-yloxy) -naphthalene-2-carboxylic acid, 1: 1 hydrochloride [6- (1-Isopropyl-piperidin-4-yloxy) -naphthalen-2-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone, [6- (1-Cyclopropyl-piperidin-4-yloxy) -naphthalen-2-yl] -morpholin-4-yl-methanone, and pharmaceutically salts acceptable of same.

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26. Compounds of formula I according to claim 1, chosen from the group consisting of (4-methyl-piperidin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (4-Isopropyl-piperazin-1-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, (3,4-dihydro-1H-isoquinolin-2-yl) - [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -methanone, [6- (3-piperidin-1-yl-propoxy) -naphthalen-2-yl] -pyrrolidin-1-yl-methanone, {6- [3- (2-methyl-piperidin-1-yl) -propoxy] -naphthalen-2-yl} -pyrrolidin-1-yl-methanone and pharmaceutically acceptable salts thereof.

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27. A process for obtaining compounds according to any one of claims 1 to 26, said process consists of a) reacting a compound of the formula II

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107

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in which R1 and R2 have the meanings defined in the claim one, with an alcohol of formula III IIIHO-A in which A has the meaning defined in the claim one,

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in the presence of a trialkylphosphine or triphenylphosphine and a diazo compound to obtain a compound of  the formula I

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108

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and yes want, convert the compound obtained into a salt of pharmaceutically acceptable acid addition or, as alternative,

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b) react compound of the formula VII

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109

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in which A has the meaning defined in the claim one, with an amine of the formula V VH-NR 1 R 2 in which R1 and R2 have the meanings defined in the claim one, in basic conditions to obtain a compound of the formula I

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110

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and, if desired, convert the Compound obtained in an acid addition salt pharmaceutically acceptable.

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28. Pharmaceutical compositions containing a compound according to any one of claims 1 to 26 as well as a pharmaceutically excipient and / or adjuvant acceptable. 29. Pharmaceutical compositions according to claim 28 for the treatment and / or prevention of diseases  associated with modulation of H3 receptors. 30. Compounds according to any one of the claims 1 to 26 for the use of substances therapeutically active. 31. Compounds according to any one of the claims 1 to 26 for the use of substances Therapeutically active for treatment and / or prevention of diseases associated with H3 receptor modulation. 32. Use of compounds according to any one of claims 1 to 26 for the manufacture of medicaments intended for the treatment and / or prevention of associated diseases with the modulation of H3 receptors. 33. The use according to claim 34 for the treatment and / or prevention of obesity.